Method of producing tranquilization by hydroxy-loweralkyl-n-substituted carbamic acid esters



May 18, 1965 v J. c. CALANDRA METHOD OF PRODUCING TRANQUILIZATION BY HYDROXYLOWERALKYL-NSUBSTITUTED GARBAMIC ACID ESTERS Filed Aug. l2. 1963 CIBLOBLOHd LNBOHBd e Blue .mwen

I 9. bve oem S2 nimm mm (W30 .LNBOHBd GBLOELOHd .LNEOHSd mmdm 2 edwoa EZ 00 O0 mmdm INVENTOR. m130 'LNBOBBd JOSEPH C. CALANDRA ATTORNEY.

METHOD OF PRODUCING TRANQUILIZATION BY HY DROXY LOWERALKYL N SUBSTITUTED CARBAMIC ACID ESTERS Joseph C. Calandra, Skokie, lll., assignor to The Pure Oil Company, Palatine, Ill., a corporation of Ohio Filed Aug. 12, 1963, Ser. No. 301,284 18 Claims. (Cl. 167-65) Various esters of carbamic acid are known to possess properties and characteristics which make them useful as pharmacological agents. The activity or effectiveness of organic compounds as pharmacological agents is, however, diicult to predict and the actual performance of one class of compounds for this purpose cannot form a basis on which to state With certainty that another class of similar compounds will also be effective. So little is known of the influence of functional groups on the pharmacological usefulness of different classes of cornpounds that research in this iield has been practically limited to a trial and error technique. Accordingly, where the effectiveness of a group of compounds or the iniiuence of a functional group on a class of compounds can be demonstrated by actual tests, an advancement in this art has been made. This application is a continuation-in-part of copending application Serial No. 176,483, filed February 20, 1962, now abandoned, the latter being a continuation-in-part of application Serial No. 781,608, iled December 19, 1958, now abandoned.

This invention is based on the discovery that a certain acid, in which the ester group contains at least one polar substituent, are useful as pharmacological agents. More particularly, it has been found that a certain class of polar esters of carbamic acid, in which the ester group contains at least one polar substituent, such as, but not limited to, the polar esters of aralkyl carbamates having from 1 to 5 carbon atoms in the alkyl portion, are useful as anti-convulsants, muscle relaxants, tranquilizers, sedatives or hypnotics and anesthetics in the treatment of vertebrates including humans at a dosage of about 150 mg. to about 3300 mg. per day or more. These cornpounds may be used as anti-leukemia agents but this property has not been established.

Broadly, the pharmacological agents of this invention are represented by the following general Formulas I wherein, in Formula I, n represents the numerals 2 through 5 inclusive, and X is an aralkyl radical having from l to 5 carbon atoms in the alkyl portion and having a phenyl or naphthyl group as the aryl portion thereof. Examples of aralkyl groups illustrating X in Formula I are benzyl, 1-phenylethyl, 2-phenylethyl, phenylisopropyl, phenyl normal propyl and isomers thereof, Z-phenylsecondary butyl, 3-phenylamyl, naphthylmethyl, l-naphthylethyl, 2-naphthylethyl, 2-naphthylsecbutyl, hydroxyphenyl, aminophenyl, and 3naphthylamyl radicals, also including fluorophenyl and the like.

United States Patent O ice Included in the foregoing definition of X are the following radicals Wherein phenyl may also be naphthyl:

3-phenyl-n-propyl CH2-onrein- 2-rnethyl-4 -phenyl-n-butyl -CHg-CH-CHg-CHV l-phenyl-n-propyl -C H-C Hg-C H3 2-phenyl-n-propyl C HV C H--C Hs l-methyl-l-phenylethyl (2-phenylisopropyl) -U--CH3 1-methyl-2-phenylethyl (1-phenylisopropyl) adsense 2-hydroxyethyl-N-1-methyl3phenylpropyl carbamate, Z-hydroxyethyl-N-l-phenyl-Z-sec-butyl carbamate, 2-hydroxyethyl-N-1,l-dimethyl-Z-phenylethyl carbamate, Z-hydroxyethyl-N-1-methyl-l-benzylethyl caroarnate, 2-hydroxyethyl-N-5-phenylnamyl carbamate, 2-hydroxyethylN-4phenylnamyl carbamate, 2-hydroxyethyl-N-3phenyl-namyl carbamate, Z-hydroxyethyl-N-Z-phenyl-namyl carbamate, Z-hydroxyethyl-N-l-phenyl-n-amyl carbamate, Z-hydroXyethyl-N-l-phenyl l-methylbutyl carbamate, 2-hydroxyethyl-N-3-phenyl-l-methylbutyl carbarnate, Z-hydroXyethyl-N-2-phenyl-l-methylbutyl carbamate, 2-hydroXyethyl-N-l-phenyl-l-methylbutyl carbamate, Z-hydroxyethyl-N-l-benzylbutyl carbamate, 2-hydroxyethyl-N-l-ethyl-3-phenylpropyl carbamate, 2-hydroxyethyl-N-di-ethylphenylmethyl carbamate, Z-hydroxyethyl-N-l-ethyl-2phenylpropyl carbarnate, 2-hydroXyethyl-N3-naphthyl-n-propyl carbarnate, 2-hydroxyethyl-N-4-naphthyl-n-butyl carbamate, Z-hydroxyethyl-N-S-naphthyl-n-amyl carbamate, 2-hydroXyethyl-Nl-naphthyl-n-propyl carbamate, Z-hydroxyethyl-N-Z-naphthyl-n-propyl carbamate, 2-hydroxyethyl-N-l-methyl-l-naphthylethyl carhamate, 2hydroxyethylNl-methyl-Z-naphthylethyl carbamate, Z-hydroxyethyl-N-l-naphthyl-n-butyl carbamate, 2-hydroXyethylN3-naphthyl-n-butyl carbamate, Z-hydroxyethyl-N-Z-naphthyl-n-butyl carbamate, Z-hydroxyethyl-N-l-naphthyl-n-butyl carbamate, 2-hydroxyethyl-N-l-methyl-l-naphthylpropyl carbamate, Z-hydroxyethyl-N-1-methyl-Z-naphthylpropyl carbamate, Z-hydroxyethyl-N-l-methyl-3-naphthylpropyl carbamate, 2-hydroxyethyl-N-l-naphthyl-Z-sec-butyl carbamate, 2 hydroXyethyl-N-l,l-dimethyl-2-naphthylethyl Carbamate, 2-hydroXyethylN-5-naphthyl-namyl carbamate, 2hydroxyethylN4r1aphthyl-n-amyl carbamate, Z-hydroxyethyl-N-3-naphthyl-n-amyl carbamate, Z-hydroxyethyl-N-2-naphthyl-n-amyl carbamate, Z-hydr-oxyethyl-N-1naphthyl-namyl carbamate, 2-hydroxyethylN4naphthyl-l-methylbutyl carbamate, 3-hydroXypropyl-N-benzyl carhamate, 3-hydroXypropylNl-phenylethyl carbamate, 4-hydroXybutyl-n-benzyl carbamate, 4-hydroxybutyl-N-l-phenylethyl carbamate, S-hydroXyamyl-N-benzyl carbamate, 5-hydroxyamyl-N-l-phenylethyl carbamate, 2-hydroxyethyl-N-Z-phenylethyl carbamate, 3-hydroxypropyl-N2phenylethyl carbamate, 4-hydroXybutyl-N-2-phenylethyl carbamate, 5hydroXyamyl-N-Z-phenylethyl carbamate, 2-hydroXyethyl-N-Z-phenylsec-butyl carbamate, 3-hydroxypropyl-N-Z-phenylsec-butyl carbamate, 4-hydroXybutyl-N-Z-phenylsec-butyl carbamate, S-hydroxyamyl-N-Z-phenylsec-butyl carbamate, Z-hydrOXyethyl-N-naphthylmethyl carbarnate, 3-hydroXypropyl-N-naphthylmethyl carbamate, 4-hydroXybutyl-N-naphthylmethyl carbarnate, 5hydroxyamyl-N-naphthylmethyl carbamate, 2hydroxyethylN3-naphthylamyl carbamate, 2-hydroxyethyl-N-2naphthylethyl carbamate, Z-hydroxyethyl-N-1-naphthylethyl carbamate, and 2hydroxyethylN2naphthylsec-butyl carbamate.

Particular preferred species under Formula I are: 2-hydroxyethyl-N-Zephenyl-n-propyl carbarnate (u) I Phenyl HO-CHz-CHg-O-C-N-CHg- H Z-hydrOXyethyl-N-l-methyl-Z-phenylethyl carbamate o CH3 HO-CHg-CHz-O- -IT- H H Hg-phenyl 6 Z-hydrOXyethyl-N- l-methyll-phenylethyl carb amate 0 C H3 H O-C Hg-C HgO-l-N---Ca phenyl 2-hydroXyethyl-N-3-phenyl-n-propyl carbamate o Ho-CHz-GH2-o--N-CHVCH-Cn-phenyl 2hydroXyethylN1phenylnpropyl carbamate o Ho-orn-onr-o-ii-N-CHQoHn-ona phenyl Species tof compounds coming under Formula II are:

Ho-CHVCHg-o-C CH,

2-hydroxyethylethyleneiminocarboxylate 2-hydroxyethyltrimethylene iminocarboxylate O HO-CHz-CHz-O-C CH2-CH2 OHV-CH2 2-hydroxyethyl-N-pyrrolidinyl carbamate O HO-CHg-CHz-O-C CH2-CH,

CH2-CH2 2-hydroxyethyl-N-piperidinyl carbamate Within the broad denition of the invention there are species which will not possess pharmacological effectiveness in the same or other areas of utility equivalent to the more active species which are used herein to demonstrate the invention. Also, the areas of utility within the pharmacological activity of all species included in the broad denition will vary. Accordingly, although a somewhat restricted area of utility will be demonstrated for certain species, it is to be understood that this demonstration in the field of pharmacology is a good indication that the compounds generally and other species Will have utility in other areas of application although the manner of administration may differ or the results detected by applying different techniques.

Accordingly, it becomes a primary object of this invention to provide a method of inducing tranquility in humans using new classes of pharmacological agents Within the genus of carbamates at a dosage of about 150 to about 3300 mg./day.

Another object of the invention is to provide a method of inducing tranquility in vertebrates including humans by administering hydroxy esters of carbamic acid.

A further object of the invention is to provide a method of counteracting convulsions in vertebrates by administeriig compositions containing hydroxy esters of carbamic acl Another object of the invention is to provide a method of counteracting convulsions and inducing tranquility in vertebrates including humans by administering intraperitoneally about 150 to about 3300 mg./day of hydroxy esters of carbamic acids having a benzyl group attached to the nitrogen atom.

Still another object of the Vinvention `is to provide aV method' of counteracting convulsions and inducing tranquility in vertebrates including humans which comprises f administering intraperitoneally about 150 to about 3300 mg./day of hydroxy esters of carbamic acids having a piperidinyl group attached to the nitrogen atom. t

Another object of the invention is to provide `a method of counteracting convulsions and inducing tranquility in vertebrates including humans by administering about 150Y to about 3300 nig/day of 2hydroxyethylNbenzyl carbamate. Y f

Still another object of the invention is to provide a method of counteracting convulsions and inducing tranquility in vertebrates byadministering 2-hyclroxyethyl-N-V piperidinyl carbamates.

A further object of this invention is to provide a methodu of inducing tranquility in vertebratesV by administering compounds of the group consisting of 2-hydroxyethyl-N-benzyl carbamate 2-hydroxyethyl-N-piperidinyl carbamate 2-hydroxyethyl-N-phenylethyl carbamate 2-hydroxyethyl-N-Z-phenyl-n-propyl carbamate 2hydroxyethylNl-methyl-Z-phenylethyl carbamate Z-hydroxyethyl-N-1-methyl-l-phenylethyl carbamate 2-hydroxyethyl-N-3-phenyl-n-propyl carbamate and 2-hydroxyethy1-N-1-pheny1-n-propyl carbamate Vinjection (l0 animals were tested).

neric formula by inducing convulsions in test animals by stimulation with strychnine (C21H22O2N2) and metrazol (C5H10N4pentamethylenetetrazol) and comparingl their effectiveness with that of a known drug which is clinically used as an anti-convulsant or muscle relaxant. Strychnine and metrazol are known to stimulate the central nervous system and, in sutlicient dosage, cause fatal convulsions. As a basis of comparisomthe ability of the carbamates of this invention to overcome suchrinduced convulsions or prevent death as a result thereof, is tested with mephenesin which is 3-o-to1yloxy 1,2-propandiol. Y

Before proceeding to test the anti-convulsive properties of the test compounds and the comparison standard of mephenesin, the LDm doses (100 percent lethal dose, i.e.,A the minimum dose level at which all of the animals injected died) of the convulsant compounds were determined. In each case, groups of ten animals were injected intra-peritoneally with doses of the'ptwo convulsant agents. The LDmo of strychnine sulfate was found/to be 3.0 mg./ kg. body weight with convulsion ensuing within one to three minutes.' The LDloo dose of metrazol given intraperitoneally'rwas established atv 100Y mg./kg. with convulsions starting within one minute.

In making the LDmo' tests and the following tests, Swiss Y male albino mice having 25 grams body weightwere used as the test animals. In the following experiments the test animals were rst injected intra-peritoneally with,

various` dosages of the test carbamates iifteen (l5) minutes prior to the injection of LDlm dosages of strychnine sulfate or metrazol.

PROTECTION AGAINST STRYCHNINE n CONVULSIONS A 2-l1ydroxyethyl-Nmorpholinyl carbamate, at adorse of 400 mg./kg., did not show any significant effect on the posture of the animalsl and did notatlord any observable protection against strychnine. Convulsions occurred without delay, and the seizure pattern was very similar to that observed with control'animals. 2-hydroxyethyl-N-piperidinyl carbamate, at a dose of 400 mg./kg., vdid not affecty animal posture to any signicant extent. While protection against lethal doses of istrychninejwas insignificant` (the mortality observed was percent), the occurrence of deathviwas delayedrin seven `cases up to ten minutes while three deaths occurred within -10 to 20 minutes after convulsive activity was observed.

YAt a dose level of 400.mg,/kg."of 2-hydroxyethyl-N-- benzyl carbamate, the animals tested showed some loss in posture'. The first strychnine-induced convulsionsv appeared in about ve minutes, which represented a delay in comparison tothe untreated animals. Only four deaths occurredv in ten Ltest animals; the majority of surviving animals appeared normal within 1.5 hours after injection. This carbamate was also testedat a dose level of 300 Ing/kg. Results of tests at both dose levels are shown in Table VI and in FIGURE l. All of the tests herein were conductedl using normal saline solutions.

Table I 2-HYDROXYETHYL-N-BENZYL i CARBAMATE PROTECTION AGAINST STRYCHNINE [Dose ofrstrychnine sulfate, 3 mg./kg. I.P.]

Protective does5n7=340 mg/kg.

The results of mephenesin tests vare shown in Table II andl FIGURE I. Y

Table `Il MEPHENESIN PROTECTION AGAINST STRYCHNINE [Dose of strychnine sulfate, 3 nig/kg. I.P.]

Dose of Number Number of Percent mephenesin, of animals deaths protected mg./kg.

Protective`Dosein=410 rug/kg.

The comparison 1 of the anti-Strychnine activitiesV of 2-hydroxyethyl-Nbenzyl carbamate and mephenesin Y(see FIGURE'r 1) shows the rst compound to be more effective onY a weight basis. 'Furthermore, the carbamate protected protected animals at dose levels which were well belowV its lethal dose level, whilel the PD50 of mephenesin appeared to be very close to its LD50.

PROTECTION VAGAINST METRAZOL-INDUCED CONVULSIONS The extents of protection afforded by mephenesin and 2-hydroxyethyl-N-benzyl carbamate against convulsions induced by metrazol injection were also determined. Results of theV mephenesin tests areV shown in Table III and FIGURE'Z.

Thus, mild anti- Table Ill MEPHENESIN PROTECTION AGAINST METRAZOL [Dose of metrazol, 100 mgJkg. I.P.]

Dose of Number of Number of Percent mephenesin, annuals deaths protected mg. /kg.

Protective Doseo=440 nig/kg.

Results of the carbamate tests are shown in Table IV and FIGURE 2.

Table IV 2-HYDROXYETHYL-N-BENZYL CARBAMATE PROTEC- TION AGAINST METRAZOL [Dose of metrazol, 100 ing/kg. LPJ

Dose of test Number of Number oi Percent earbamate, animals deaths protected mgjkg.

Protective Dose5u=190 nig/kg.

At mep'nenesin dose levels of 400 and 420 mg./ kg., the injection of metrazol did not cause any significant convulsions for some time except o-r a few twitches of the extremities. Following a 30 to 40 minutes latent period, convulsions began to appear, the animals exhibited Straubtail effect, and mouth bleeding was common. Surviving animals appeared to have returned to normal after two to three hours; most of the deaths occurred within one to one and one-half hours after metrazol injection.

At a 2-hydroxyethyl-N-benzyl carbamate dose level of 400 mg./ kg., clonic convulsions occurred two minutes after metrazol injection. Animals showed distinctive hyperactivity, automatic leg movements, jumping, :and Straubtail elect. Hyperactivity continued for about two hours, but no deaths occurred at this dose level, at lower dose levels there was proportionately less protection as evidenced by the severity of convulsions and the shortening of survival times.

The superiority of 2-hydroxyethyl-N-benzyl carbamate over mephenesin in protecting against metraZol-induced convulsions is demonstrated by FIGURE 2. The PD50 of mephenesin was 440 ing/kg.

The foregoing tests have shown that 2hydroxyethy1N scope of this invention are readily prepared by the reaction of a suitable cyclic glycol carbonate with an amine such as benzylamine or piperidine to illustrate the preferred examples. Thus 2-hydroxyethyl-N-benzyl Carbamate is prepared by gradually introducing about 500 gms. or' benzylamine and about 400 gms. of cyclic carbonate of glycol into a vessel equipped with a stirrer and which is jacketed so that the temperature can be maintained at about 40 C. during initial mixing. The reaction mixture is maintained at 40 to 50 C. for about 10-l2 hours. A white crystalline mass of Z-hydroxy-ethyl-N-benzyl carbarnate settles out on cooling the mixture. After purification by repeated recrystallizations, the product has a melting point of about 40 C. By a similar reaction, piperidine is reacted with cyclic carbonate of glycol to form 2-hydroxyethyl-N-piperidinyl carbamate. This product is distilled at reduced pressure and boils at ll-162 C. under a pressure of l5 mm. of mercury. Substituting piperazine hydrate for piperidine and doubling the mole ratio used with the glycol carbonate produces Z-hydroxyethylpiperazine dicarbamate which may also be used as an anti-convulsant.

The process of administering the hydroxy alkyl esters of N-arallryl carbamates of this invention may be conducted by treating the living organism, animal organism, Inammalian or vertebrate animal or human being with cornpositions containing the carbamates or properly buffered solutions of the carbamates in safe therapeutic dosages. The carbarnates of this invention may be administered orally, intra-peritoneally, intra-muscularly, intravenously or by other known routes. Various types of carrier vehicles may be used, including normal saline solutions, and other properly buffered aqueous vehicles. The concentrations used should be below lethal dosage as indicated from the experiments. When oral administration is used the carbamates may be tableted with starch or lactose in the known manner and using various proportions of ingredients for different dosages as desired.

In order to establish the tranquilizing and anti-convulsant properties of the compounds coming within the scope of the invention, clinical tests were conducted by an independent clinic on 18 patients using Z-hydroxyethyl- N-benzyl carbamate. In this series of tests the average effective dose was mg. Q.I.D. (4 times daily). The largest eiective dose used was 120 mg. Q.I.D. and the smallest effective dose was 60 mg. TLD. (3 times daily). The results are shown in the following table which indicates the other drugs with which the patients had been treated prior to the clinical tests, the diagnosis of each patient, the electroencephalogram reading for each patient, the duration of treatment and the clinical results.

Table V Other drugs Patient Diagnosis EE G Duration of Results treatment 1 Hypothalamio seizures 14-1-6 per second pos. spikes.-. 3 mos Excellent. Celontiu 2 Petit mal- 2+3 per second spike and wav Poor.

3 2|3 per second spike and wave Excellent 4 4+6/sec Good. 5 4+6/see Do. 6 l-i-/seo Excellent. 7 do 2-l-3/see Good. Dilantin 8 Grand mal Spfike and wave multiple rapid spike Fair.

oci. 9 Infantile myoelonic spasms. Hypsarrhythmia 12 Weeks Good. Gemonil 10 do do 12 weeks Do.

11 Grand mal Rapid spikes, diirusem 12 weeks Poor. Phenobarbital 12 Grand mal and Petit mal Mixed dysrhythmia Fair. Dilantin 13 Petit mal variant Grand mal.. Diffuse dvsrhythmia Poor.

14 Hypothalamio seizures 14-l-G/see pos. spikes Excellent. 15 Grand mal Dituse rapid spikes No follow up. 16 Hypothalamic seizures- M+S/see pos. spikes Excellent. 17 Hyperkinetie syndrome Nonspeeitic dysrhythmia 4+7/see Do. 18 do Non-spec. dysrhythmia 3 Do.

benzyl carbamate has superior anti-convulsive properties, that 2-hydroxyethyl-N-piperidinyl carbamate had mild but effective anti-convulsive activity and Z-hydroxyethyl-N- morphinyl carbamate has no observable protection against strychnine-induced convulsions.

Hydroxy esters of carbamic acid coming within the The results of these tests indicate a reliable effectiveness in hypothalamic seizures, good results in petit mal and the hyperkinetic syndrome. The results with regard to grand mal and infantile myoclonic spasms are encouraging. None of the patients treated showed any ill effects or evidences of toxity during treatment.

1 1 Y The drug Celontin (a proprietary product) lwith which patient No. 2 had previously been treated is N,2phenylsuccinimide having the formula C12H13NO2 and a molecular weight of 203.23. The known medical use for this drug is 'the treatment of petit mal and psychomotor epilepsy.

Thedrug Dilantin (a proprietary product)'with which patient Nos. 8 and-13 had previously been treated is 5,5- diphenylhydantoin sodium having the formula and a molecular weight of 274.25. This drug is commonly used as an anticonvulsant for grand mal epilepsy;

I The drug Gemonil (a proprietary product) previously used for patient No. 10 is 5,S-diethyl-l-methylbarbituric acid having the formula C9H14N2O3 and a molecular weight of 198.22.V This drug Vis an anticonvulsant which is effective in controlling seizure phenomena associated with organic brain disease.

The drug Phenobarbital (-a proprietary product) previously used by patent No. 12 is 5-ethyl-5-phenylbarbituric acid having the formula C12H12N2O3 and a molecular weight of 232.23. Y

Fifty-four patients in the l,pediatric age group were treated 'over a one-yearl period at the Pediatric Neurology Clinic of Mercy Hospital in Chicago, Illinois. Eleven of n the patients had hypothalamic seizures, thirteen had petit mal seizures, six had infantile myoclonic seizures, six had grand mal seizures, three had psychomotor yseizures and fifteen had the so-called hyperki'netic syndrome. VAll patients were administered the compounds of this invention in doses ranging from 200101600 mg. per day in three to four divided doses. Y l

VAll patients had week-ly urinalyses and complete blood counts for the rst six month-s and bi-weeldy determina-V tions for the second six months of therapy. Monthly liver function examination, by means ofcephalin occulation and/or bromsulfalein excretion tests,.was also carried out. Careful interval histories were taken at each examination and untoward reactions such as skinV eruptions and gastrointestinal complaints were promptly investigated. Results are summarized in Table VI.

Table VI yCUMULATIVE RESULTS f Y [Use of 2-hydroXyethyl-n-benzyl carbamate for a 12-month period] time.

The drug demonstrated a striking effectiveness in hypothalamic seizures andthe hyperkinetic syndrome. Hypothalamic seizures have a good prognosis a-s to-improvement with yadvancing age but control is important both to avoid unnecessary therapy for psychosomatic equivalents which accompany this disorder and yalso to avoid the serious rbehavior disorders which may characterize these seizures. Thek dramatic eifect of the compounds of this invention may best be illustrated by the following case of hypothalamic dysfunction.

A 12-year-old White malewhose electroencephalogram showed 14 and 6 percent positive spikes was given a course of 100 mg. of diphenylhydantoin ourtimes daily for 2 weeks with-out improvement. He was Istarted on 2- hydroxyethyl-N-benzyl carbamate, 400 mg. four times a day with dramatic improvement. Reduction of -the 2- hydroxyethyl-N-benzyl carbamate to 200 mg. three times a day resulted in partial return of symptoms. Since being kon therapy, the boy has returned to normal health;

In another clinical case aten-year-old girl had intermittent abdominal pains lasting from minutes to hal-f an hour. These pains carne on suddenly causing the patient to double up. An,=appendectorny revealed la normal appendix and lthe symptoms continued unabated. She was placed on 100 mgms. of Dilantin in the morning and 100 mgms. at bedtime along with 32 mgm-s. of Phenobarbital at bedtime which did reduce the frequency and severity of her attack-s. The Dilantin Vwas gradually increased in mgm. increments until she was taking mgms. of Dilantin a `day and 64 mgms. of Phenobarbital at bedtime, same beingthe-maximal ldosages she could tolerate. On this 4dosage lthe pains were no less than they had been on the original amount and continued so severe that she was unable to attend school. Her electroencephalographic tracing showed frequent bursts `of 14 and 6 percent positive spiking in the right -or .left temporal occipital` areas in sleep.

She wasstarted on 100 mgms. of 2-hydroxyethyl-N- benzyl carbamate threertirnes a day and since this treatment she has .attended school and experiences only mild dis-comfort. There was also a marked change in the appearance of the child and all evidence of pain vanished after, one week of treatment. The Dilantin was gradually reduced toV only 100 mgms; in the morning and at bed- This reduction was continued WhileV the dosage of Z-hydroxyethyl-N-benzyl carbamate was increased It-o 100 mgms. four times a day with no signs of recurrence lof the pain 4and otherwise completely normal and healthy symptoms being apparent.`

From the tests on laboratory animals and the conrmatory tests on humans the utility lof the compounds of this inventionY for the purposev of counteracting convulsions and inducing tranquil-ity in vertebrates has been demon- No. patients Avg. length Results treated of therapy t Hypotha-lamie seizures (6 11 6 mos Excellent 10 and 14 per second positive Good 1 spikes on EE G). Falr 0 Poor 0 Petit mal seizures (3 per 13 8 mos Excellent 6 second spike and Wave oo 4 pattern on EEG). Fair 2 Poor 1 Infantile myoclonic 6 6 mos Excellent 0 seizures (Hypsarrhy- Good 2 thmia on EE G). Falr 3 Poor 1 [All patients with Hypsarrhythmia were given a course of ACTH, in

addition to 2-hydroxyethyl-n-benzy1 carbamate. The combination.

appeared to be superior to ACTH alone] Hyperkinetic syndrome 15 8mos ..v Excellent 9 f (non-specific dysrthyth- Good 5 rnia or no abnormality Fan' 1 on the EE G). Poor 0 Grand mal seizures 1 6 2 mos Excellent 0 (Rapid spike patterns f M Good k 0 on EEG). e Fair 1 Poor 5 [2 cases were thought tolhavo been aggravated by Z-hydroxyethyl-nbenzyl carbamate] Excellent strated, particularly in relation to the'relief of hypothalamic seizures, petit mal and hyperkinetic syndromer in humans when administered in multiple doses at total dos- -ages of about 150 to yabout 3300 mg./ day and preferably' fat a total'idosager of about 180 to about. 2000 mg./day. For some patients a dosage of about 50 to 60 mg. administered three times daily Will sutce and in others a dosage f of about mg. administered four times daily will be necessary., The average patient Willrespond to a dosage of about 60 mg. administered four times a day. The

"foregoing'considerations of dosage also apply to patients suering from grand mal Aand infantile nyoclonic spasms. These total dosages for humansmay be increased beyond 2000 mg. per day to as high as 3300 mg. per day (orabout `,50 grains per` day) to induce tranquility in severe cases without danger of toxicity or other after effectsl A minimum dosage unit of about 25 mg. canfbe used.

The embodiments of the invention in which an exclusive property or privilegeis claimed are dened as follows: 1. The method of inducing tranquility in vertebrates which comprises administering about to about3300 mg./day of compounds of the groupconsisting of hy- 13 droxy alkyl esters of N-substituted carbamates of the formulae wherein n is an integer of from 2 to 5 and X is .a member of the group consisting of phenylalkyl and naphthalkyl having from 1 to 5 carbon atoms in the alkyl and (II) H-(CHg) n-O-C wherein n is an integer of from 2 to 5 and R is divalent alkylene of 2 to 5 carbon atoms.

2. The method in accordance with claim 1 in which, in Formula I, X is benzyl.

3. The method in accordance with claim 1 in which, in Formula II, R is cyclopentyl.

4. The method in accordance with claim 1 in which, in Formula I, n is 2 and X is benzyl.

5. The method in accordance with claim 1 in which, in Formula II, nis 2 and R =is cyclopentyl.

6. The method in accordance with claim 1 in which, in Formula I, X is l-phenylethyl.

7. The method in accordance with claim 1 in which, in Formula I, X is 2-pheny1ethy1.

8. The method in accordance with claim 1 in which, in Formula I, X is phenyl n-propyl.

9. The method in accordance with claim 1 in which, in Formula I, X is phenyl isopropyl.

10. The method in accordance with claim 1 in which, in Formula I, X is 1-methyl-2-phenylethyl.

11. The method in accordance with claim 1 in which, in Formula I, X is 1-methyl-1-phenylethyl.

12. The method in accordance with claim 1 in which, in Formula I, X is 1-methy1-2-phenylethyl.

13. The method in accordance with claim 1 in which said compounds are administered at a dosage of about 150 to yabout 3300 mg./ day.

14. The method in accordance with claim 13 in which said compounds are administered at a dosage of about 60 mg. to about 825 mg. 3 to 4 times daily.

15. The method of inducing tranquility in humans which comprises administering about 150 to about 3300 mg./ day of Z-hydroxyethyl-N-benzyl carbamate.

16. The method in accordance with claim 15 in which said dosages are administered at a dosage of mg. to 825 mg. 3 to 4 times daily.

17. The method of inducing tranquility in humans which comprises administering about to 3300 mg./ day of 2-hydroxyethyl-N-piperidinyl carbamate.

18. The method in accordance with claim 17 in which said doses are administered at a dosage of 60 mg. to 825 mg. 3 to 4 times daily.

References Cited bythe Examiner UNITED STATES PATENTS 12/54 Kaiser 260-471 3/8 Viard 260-471 OTHER REFERENCES Laurence: British Med. I., Mar. 22, 1958, pp. 700-702, 167-65.

Charonnat: Ann. Pharm. Franc., vol. 11, 1953, pp. 409-414, as obtained through Chem. Abst., vol. 47, 1953, page 13759.

Hazard: Ann. Franc., vol. 9, 1951, pp. 390-397, as obtained through Chem. Abst., vol. 46, 1952, p. 1160.

Seevers: U. Mich. Bull. September 1957, p. 53.

American Druggist, Mar. 24, 1957, p. 53.

Amer. Jour. Pharm., January 1955, pp. 14-15.

Goodwin: The Pharmaceutical I. vol. 181, No. 4952, Sept. 27, 1958, pp. 233-235.

Riley: The I. of Pharm. and Pharmacol., November 1958, pp. 657-671.

Aacra: Arch. Int. Pharm. XVIII, Nos.1-2, pp. 1-8, 1958.

Toman: Vol. 28, pp. 409-432, October 1948.

Weaver: I. Am. Pharm. Assoc., vol. 47, No. 9, pp. 645- 648, September 1958.

Slater: I. of Pharm. and Exper. Therap., vol. III, No. 2, p. 182, June 1954.

LEWIS GOTTS, Primary Examiner.

FRANK CACCIAPAGLIA, IR., Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OE CORRECTION Patent No. 3,184,382 May 1s, 196s Joseph C. Calandra It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column Z, lines 66 to 72, the formula should appear as Shown below instead of as in the patent:

column 8, line 36, in the footnote of Table I, for "does" read dose line 65, strike out "protected", second occurrence; column ll, line 2l, for "patent" read patient column l2, line 35, for "percent" read per second g column 13, lines ll to 14, the formula should appear as shown below instead of as in the patent:

Ho- (CH2) -n-o-C/ Signed and sealed this 16th day of November 1965.

(SEAL) Attest:

ERNEST W. SWIDER EDWARD J. BRENNER Attesting Officer Commissioner of Patents 

1. THE METHOD OF INDUCING TRANQUILITY IN VERTEBRATED WHICH COMPRISES ADMINISTERING ABOUT 150 TO ABOUT 3300 MG./DAY OF COMPOUNDS OF THE GROUP CONSISTING OF HYDROXY ALKYL ESTERS OF N-SUBSTITUTED CARBAMATES OF THE FORMULAE 